Mechanism of Tolerance to Proinsulin in NOD mice (#200)

We have shown that
transgenic over expression of proinsulin
completely protect NOD (NODPI) mice from insulin and diabetes. However, the mechanism of tolerance is not clear. We
tracked the development of insulin specific T cells in NOD and NOD NODPI mice. We have shown by transgenic overexpression of IGRP
in NOD (NODIGRP) can eliminate IGRP specific T cells, but surprising we could
still detect insulin specific T cells in NOD PI mice. There was no
significant difference in the absolute number of insulin-specific CD8+
T-cells in NOD and NODPI mice. INS-specific CD8+ T-cells in NOD mice
expanded significantly more in response to stimulation by peptide compared to
NODPI. Insulin specific in-vivo cytotoxic activity in NODPI was reduced
compared to NOD. The absolute number of INS-specific CD4+ T-cells
was decreased in NODPI mice as compared to NOD mice. INS-specific CD4+
T cells in the NOD and NODPI were tested on whether they could help CD8+
T-cells mediate diabetes. NODRAG1-/-/8.3 developed diabetes rapidly
after NOD CD4+ T-cells were transferred (median=32days). 7/8 of
recipients did not develop diabetes when NODPI CD4+ T-cells were
transferred. In a NOD mouse tolerant to proinsulin, insulin-specific CD4+
and CD8+ T-cells were detected but were not functional.